Myocardial ischemia creates autonomic nervous system imbalance and can trigger cardiac arrhythmias. We hypothesized that neuromodulation by spinal cord stimulation (SCS) will attenuate local cardiac sympathoexcitation from ischemia-induced increases in afferent signaling, reduce ventricular arrhythmias, and improve myocardial function during acute ischemia. Yorkshire pigs ( = 20) were randomized to SCS (50 Hz at 200-μs duration, current 90% motor threshold) or sham operation (sham) for 30 min before ischemia. A four-pole SCS lead was placed percutaneously in the epidural space (T-T), and a 56-electrode mesh was placed over the heart for high-resolution electrophysiological recordings, including activation recovery intervals (ARIs), activation time, repolarization time, and dispersion of repolarization. Electrophysiological and hemodynamic measures were recorded at baseline, after SCS/sham, during acute ischemia (300-s coronary artery ligation), and throughout reperfusion. SCS ) reduced sympathoexcitation-induced ARI and repolarization time shortening in the ischemic myocardium;) attenuated increases in the dispersion of repolarization; ) reduced ventricular tachyarrythmias [nonsustained ventricular tachycardias: 24 events (3 sham animals) vs. 1 event (1 SCS animal), < 0.001]; and ) improved myocardial function (dP/d from baseline to ischemia: 1,814 ± 213 to 1,596 ± 282 mmHg/s in sham vs. 1,422 ± 299 to 1,380 ± 299 mmHg/s in SCS, < 0.01). There was no change in ventricular electrophysiology during baseline conditions without myocardial stress or in the nonischemic myocardium. In conclusion, in a porcine model of acute ventricular ischemia, SCS reduced regional myocardial sympathoexcitation, decreased ventricular arrhythmias, and improved myocardial function. SCS decreased sympathetic nerve activation locally in the ischemic myocardium with no effect observed in the normal myocardium, thus providing mechanistic insights into the antiarrhythmic and myocardial protective effects of SCS. In a porcine model of ventricular ischemia, spinal cord stimulation decreased sympathetic nerve activation regionally in ischemic myocardium with no effect on normal myocardium, demonstrating that the antiarrhythmic effects of spinal cord stimulation are likely due to attenuation of local sympathoexcitation in the ischemic myocardium and not changes in global myocardial electrophysiology.

Inherent and acquired factors determine the integrated autonomic response to cardiovascular stressors. Excessive sympathoexcitation to ischemic stress is a major contributor to the potential for sudden cardiac death. To define fundamental aspects of cardiac-related autonomic neural network interactions within the thoracic cord, specifically as related to modulating sympathetic preganglionic (SPN) neural activity. Adult, anesthetized Yorkshire pigs ( n = 10) were implanted with penetrating high-density microarrays (64 electrodes) at the T2 level of the thoracic spinal cord to record extracellular potentials concurrently from left-sided dorsal horn (DH) and SPN neurons. Electrical stimulation of the T2 paravertebral chain allowed for antidromic identification of SPNs located in the intermediolateral cell column (57 of total 1,760 recorded neurons). Cardiac stressors included epicardial touch, occlusion of great vessels to transiently alter preload/afterload, and transient occlusion of the left anterior descending coronary artery (LAD). Spatial/temporal assessment of network interactions was characterized by cross-correlation analysis. While some DH neurons responded solely to changes in preload/afterload (8.5 ± 1.9%) or ischemic stress (10.5 ± 3.9%), the majority of cardiovascular-related DH neurons were multimodal (30.2 ± 4.7%) with ischemia sensitivity being one of the modalities (26.1 ± 4.7%). The sympathoexcitation associated with transient LAD occlusion was associated with increased correlations from baseline within DH neurons (2.43 ± 0.61 to 7.30 ± 1.84%, P = 0.04) and between SPN to DH neurons (1.32 ± 0.78 to 7.24 ± 1.84%, P = 0.02). DH to SPN network correlations were reduced during great vessel occlusion. In conclusion, increased intrasegmental network coherence within the thoracic spinal cord contributes to myocardial ischemia-induced sympathoexcitation. NEW & NOTEWORTHY In an in vivo pig model, we demonstrate using novel high-resolution neural electrode arrays that increased intrasegmental network coherence within the thoracic spinal cord contributes to myocardial ischemia-induced sympathoexcitation.

The pathological consequences of ischemic heart disease involve signaling through the autonomic nervous system (ANS). While early activation may serve to maintain hemodynamic stability, persistent aberrant sympatho-excitation contributes to the development of lethal arrhythmias and heart failure. We hypothesize that as myocardium reacts and remodels to ischemic injury over time, there is an analogous sequence of gene expression changes in the thoracic spinal cord dorsal horn, the processing center for incoming afferent fibers from the heart to the central nervous system. Acute and chronic myocardial ischemia (MI) was induced in a large animal model of Yorkshire pigs and the thoracic dorsal horn of treated animals, along with control non-ischemic pigs, was harvested for transcriptome analysis. We identified 32 differentially expressed genes between healthy and acute ischemia cohorts and 46 differentially expressed genes between healthy and chronic ischemia cohorts. The canonical immediate early gene (IEG) c-fos was up-regulated following acute MI along with fosB, dusp1, dusp2, and egr2. Following chronic MI, there was a persistent yet unique activation of immediate early genes including: fosB, nr4a1, nr4a2, nr4a3, egr3, and tnfaip3. In addition, differentially expressed genes from the chronic MI signature were enriched in pathways linked to apoptosis, immune regulation, and a stress response. These findings support a dynamic progression of gene expression changes in the dorsal horn with maturation of myocardial injury and they may explain how early adaptive ANS responses can maintain hemodynamic stability while prolonged maladaptive signals can predispose patients to arrhythmias and heart failure.

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Acute myeloid leukemia (AML) often requires long-term intensive chemotherapy for its cure. During chemotherapy, the patient always experiences neutropenia with readings below 500 cells/μL; this is often accompanied by pyrexia with a temperature of more than 101°F. This combination of neutropenia and fever is called febrile neutropenia (FN). A tool to sum up the daily severity of a patient’s neutropenia, the “D-index,” has been validated in some specific clinical settings. In this study, we examined whether the D-index is a useful predictor of the onset of FN. We recruited consecutive patients treated with induction and consolidation chemotherapy for newly diagnosed AML. We gathered all the FN events and their clinical background data retrospectively. Patients’ background, such as pre-existing conditions and disease status before the treatment, were analyzed using multivariate methods. All FN events during chemotherapy were evaluated for infection focus and causative organism. A total cohort of 51 cases (25 women, 26 men; median age 51 years, range 18–74) was analyzed. They displayed 171 neutropenic events (115 FN and 56 afebrile episodes) during chemotherapy, and complete neutropenic events were used in this study. Sensitivity and specificity analysis showed that the most useful cutoff value to predict the onset of FN was a cumulative D-index at day 11 (c-D11-index) of 718. The cumulative incidence of FN during chemotherapy was significantly higher in the group with c-D11-index ≥710 (80%) than in the group with c-D11-index <710 (39%) (P < 0.0001). Through multivariate analysis, the presence of diabetes mellitus and the c-D11-index were extracted as contributing factors to the onset of FN (P = 0.0087 and 0.0002, respectively). In conclusion, we can predict that AML patients receiving chemotherapy will experience the complication of FN when the c-D-index at day 11 is >710, with an odds ratio of 2.1.

Background: Platinum derivatives play important roles in salvage chemotherapy of malignant lymphoma, but may cause renal dysfunction. We examined the influence of pretransplant platinum-based chemotherapy on renal function and outcomes after allogeneic hematopoietic cell transplantation (HCT) for lymphoma. Methods: This retrospective study cohort included 229 adult patients with malignant lymphoma who had a first allogeneic HCT between 2000 and 2014 at our center. We collected cumulative doses of cisplatin (CDDP) and carboplatin (CBDCA) before allogeneic HCT, and daily renal function (eGFR) during the first 100 days after HCT. Risk factors for renal injury (eGFR <75 ml/min/1.73 m 2) are examined using logistic models. Changes in renal function between the groups were conducted by the repeated measures ANOVA. Non-relapse mortality rates were compared with the Gray test. Results: 145 patients were males and 84 females. The median patient age was 49 years (range, 19-67). Patients were divided into three groups according to the cumulative dose of each platinum agent: no CDDP (n = 129), CDDP ≤275 mg/m 2 (n = 50) and >275 mg/m 2 (n = 50); and no CBDCA (n = 111), CBDCA ≤1200 mg/m 2 (n = 77) and CBDCA >1200 mg/m 2 (n = 41). Proportions of patients with pretransplant renal injury were 32% in no CDDP group, 36% in CDDP ≤275 mg/m 2 group, and 70% in CDDP >275 mg/m 2 group (P < .01). Proportions did not differ statistically according to cumulative CBDCA doses. Multivariate analysis showed that cumulative CDDP doses >275 mg/ m 2 , aggressive and highly aggressive B cell lymphoma, and patient age ≥50 years were associated with pretransplant renal injury. Changes in eGFR across time after HCT are shown in Figure 1. Repeated measures ANOVA showed significant differences in between-subject factor and within-subject factor between no CDDP group and CDDP >275 mg/m 2 group. Between no CDDP group and CDDP ≤275 mg/m 2 group, there was a significant difference in within-subject factor and interaction. Pretransplant renal injury was associated with a trend for higher 2-year nonrelapse mortality rates (17% versus 10%, P = .12). Proportions of renal-related causes of death were higher among patients with pretransplant renal injury than those with normal renal function (34% versus 13%, P = .02). Conclusion: We should pay attention to pretransplant cumulative CDDP doses in patients with malignant lymphoma who are eligible for allogeneic HCT. Our results may support avoidance of CDDP use for these patients. CBDCA could have less influence on renal injury than CDDP.